Biology subjects

Ma, Z.

Publications and source records attributed to Ma, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Beyond Generic Signal Peptides: ApexSP Enables Cargo-Specific Secretion Design

Recombinant proteins are widely used in biopharmaceuticals, industrial manufacturing, and molecular diagnostics; however, efficient secretion remains a major bottleneck limiting their large scale production. As core elements controlling protein entry into secretion pathways, signal peptides do not function solely based on their own sequences, but rather depend on coordinated compatibility among cargo protein properties, secretion pathways, and host backgrounds. Current signal peptide engineering mainly relies on a limited number of commonly used signal peptides, empirical selection, and individual experimental screening, making it difficult to design efficient secretion elements tailored to specific expression systems. Here, we present ApexSP, a signal peptide design framework for secretion engineering tailored to individual cargo proteins. ApexSP is built upon a large scale, high quality signal peptide knowledge base and integrates a discrete diffusion generative model constrained by evolutionary information, a multitask biological filter incorporating topology information, and a signal peptide and mature protein compatibility ranking model to enable integrated design of signal peptides for specific expression systems. ApexSP achieved high accuracy in multiple attribute prediction tasks, including pathway classification and cleavage site prediction, reaching or exceeding the performance of existing signal peptide prediction tools. Moreover, the cargo protein aware ranking module improved the enrichment of candidates with high secretion performance. Experimental validation across multiple eukaryotic and prokaryotic expression systems demonstrated that screening only 10 candidate sequences generated by ApexSP yielded multiple designed signal peptides outperforming reference signal peptides, with the best performing design in the ApGA expressed Pichia pastoris system achieving a 1.71 fold increase in secretion performance compared with the factor signal peptide. Overall, ApexSP advances signal peptide research from sequence prediction toward secretion element design, demonstrating that a single round of designed signal peptides can achieve high secretion performance suitable for further engineering optimization.

synthetic biology↗

bioRxiv2026

Phenotype-driven de novo molecular design from gene expression signatures

AO_SCPLOWBSTRACTC_SCPLOWTarget-based and structure-guided drug design remain central to modern drug discovery, but complementary strategies are needed when predefined targets or binding pockets do not fully capture disease biology. Gene-expression signatures provide scalable system-level readouts of disease and perturbation states, making them attractive inputs for phenotype-guided molecular design. However, preserving phenotypic information during molecular generation remains challenging, and chemically plausible molecules may lose connection to the intended biological response. Here, we present Tx2Mol, a transcriptome-guided framework that translates gene-expression signatures into candidate molecules while maintaining biological guidance throughout generation. We evaluated Tx2Mol across three biological settings: bulk gene perturbation, single-cell perturbation, and patient-derived disease signatures; and three validation dimensions: chemical plausibility, structural compatibility, and phenotypic preservation. Across 10 cancer-relevant bulk gene-perturbation benchmarks, Tx2Mol outperformed 9 transcriptome-guided baselines, improving maximum Tanimoto similarity to known ligands by 24.10% on average and by 50.67% on HDAC1. Structure-based analyses further supported structurally novel candidates with favorable predicted target binding. Tx2Mol also generalized to noisy single-cell perturbation profiles and preserved drug-induced transcriptional responses through in silico drug-perturbation validation. Patient-derived disease signatures further guided molecular generation toward approved-drug chemical space. Together, these results support gene-expression phenotypes as actionable guidance signals for phenotype-directed molecular design and candidate prioritization.

bioinformatics↗

bioRxiv2026

Chemotherapy-induced multicellularity drives drug-tolerant persistence state in tumor cells

Multicellularity is a well-documented microbial response to stress, however its role as an adaptive survival strategy in cancer remains unresolved. Here we reveal that drug stress, such as paclitaxel treatment, enable rapidly (within 24-48 hours) and efficiently ([~]20-40%) convert single mouse breast 4T1 cancer cells into clonal multicellular spheroids, ultimately generating multicellular masses. Notably, multicellularity is reversible: upon stress removal, most of them restore a unicellular lifestyle that quickly becomes dominant. This transient multicellular state shields cells from hostile niches, functions as a drug-tolerant persistence (DTP) reservoir, and fuels post-therapy relapse, revealing multicellularity as a facultative evolutionary pivot for fitness gain. Importantly, blocking primordial germ cell (PGC) specification suppresses the multicellularity transition. Our findings reveal that certain cancer cells enable adopt unicellular-multicellular life cycle through phenotypic plasticity, dynamically adapting to microenvironmental shifts to maximize fitness. This discovery reframes cancer evolution and the drug-tolerant persistence (DTP) state, highlighting multicellularity as an adaptive, stress-inducible survival strategy against therapy. HighlightO_LIDrug induced evolution from unicell to clonal multicellularity. C_LIO_LIProviding a novel DTP state. C_LIO_LIRevealing environment-dependent bistable plasticity: multicellular persistence (stress) versus unicellular proliferation (favorable). C_LIO_LIBlocking primordial germ cell (PGC) specification suppresses the multicellularity. C_LI

cancer biology↗

bioRxiv2026

Internalized Components of Membrane Attack Complexes Disrupt Proteostasis and Acquire Alarmin-Like Properties

Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-{kappa}B. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo, and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-{kappa}B -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.

biochemistry↗

bioRxiv2026

Fault-tolerant 3D reconstruction from 2D spatial proteomics sections

Reconstructing 3D molecular volumes from sparsely sampled 2D tissue sections is limited by per-section marker dropout and tissue loss. We present 3D-Omics-Flow, a generative pipeline that jointly repairs damaged sections and interpolates between them at single-cell resolution. Across datasets spanning health and disease, 3D-Omics-Flow expands 3D spatial proteomics to practical sampling regimes, enabling atlas construction and downstream analysis from imperfect 2D section stacks.

bioinformatics↗

bioRxiv2026

Spatial atlas highlights contribution of C. difficile in early-stage colorectal cancer

Background and AimsIntratumoral heterogeneity with respect to both host and microbial components has emerged as an important contributor to colorectal cancer (CRC) biology. Although the overall taxonomy and abundance of the CRC tumor microbiome have become well characterized, much less is known about bacterial niches within the tumor microenvironment (TME). Escherichia coli and Fusobacterium nucleatum are highly prevalent and abundant species linked to CRC. Less abundant organisms, like Clostridioides difficile and Enterocloster aldenensis, are emerging as potentially important CRC-associated bacteria. Additionally, many studies are confounded by preoperative oral antibiotics or the inclusion of late-stage cancers, both of which may alter the gut microbiome. To better understand the spatial relationships between bacteria and CRC, we generated a molecular atlas based on surgically resected tissue specimens collected from a unique cohort of early-stage CRC patients in whom oral antibiotics were not administered preoperatively. MethodsFrom 20 CRC specimens, we performed matched histopathological analysis, fluorescence in situ hybridization (FISH), whole exome sequencing (WES), 16S rRNA amplicon bacterial DNA sequencing, codetection by indexing (CODEX) multiplex immunofluorescence, and spatial transcriptomics of 756 regions among the specimens. We used 16S rRNA amplicon sequencing data to design and experimentally validate custom bacterial probes that were applied to the spatial transcriptomics. Human colonic organoids were used to validate the relationship between Clostridioides difficile toxin B (TcdB) and an E-twenty-six family transcription factor, ELF3. ResultsWe identified eight intratumoral bacterial niches consisting of a variety of bacterial species, and each niche was associated with unique tumor features. We further defined tumor gene expression patterns correlating with individual bacterial species and show that C. difficile has a disproportionate impact on the tumor transcriptome given its relatively low abundance. Specifically, TcdB induces nuclear localization of ELF3, increased cytosolic {beta}-catenin protein, and upregulated WNT signaling. ConclusionOur study integrates multi-omics to identify bacterial species with biological and spatial relevance in CRC regardless of abundance. These findings will enable further studies to define diagnostic and therapeutic targets for bacteria-associated CRC.

Cancer Biology↗

bioRxiv2026

Long-read RNA-seq resolves isoform-level and context-specific regulatory architecture of complex traits in cattle

Traditional short-read RNA-seq lacks the resolution to fully capture full-length isoforms and complex alternative splicing, leaving a "missing regulation" gap in existing molecular atlases. Here, we present a population-scale, multi-omics dissection of bovine complex traits using matched deep whole-genome sequencing (30x), long-read (ONT) and short-read RNA-seq, as well as metabolome data from 432 dairy cows across four distinct lactation stages. We expanded the bovine transcript atlas with 13,177 novel isoforms and fine-mapped 1,088,900 regulatory effects across 11 diverse molecular phenotypes. Notably, long-read mapping uncovered 606 genes with isoform expression quantitative trait loci (12.8%, eQTL) and 1,116 genes with detailed splicing QTL (sQTL) (31.8%) that were missed by conventional short-read mapping. We further showed that lactation-specific regulation was profoundly mediated by the metabolic microenvironment (46.8%) and cellular composition (4.3%). Across genome-wide associations (GWAS) of 90 bovine complex traits, isoform-level and context-specific regulatory effects captured GWAS loci missed by short-read eQTL and sQTL analyses, increasing colocalized loci from 35.2% to 60.3%. These regulatory variants also exhibited evolutionary constraints with human immune and metabolic loci. Our study establishes an invaluable resource (https://cattleblr.farmgtex.org) demonstrating that long-read transcriptomics is essential for resolving the complexity of regulatory mechanisms underlying mammalian physiology.

genetics↗

bioRxiv2026

Microbiota-derived TMAO links PM2.5 exposure to cognitive impairment: A gut liver brain axis

Although fine particulate matter (PM2.5) is linked to cognitive impairment, the mechanistic links between pulmonary exposure and neurodegeneration remain poorly understood. This study investigates the role of the gut-liver-brain axis in mediating PM2.5-induced neurotoxicity. We demonstrate that three weeks of intratracheal PM2.5 instillation in mice causes significant memory deficits, impaired hippocampal adult neurogenesis, and reduced synaptic plasticity in both sexes. Metagenomic analysis revealed that PM2.5 alters gut microbiota composition, specifically by upregulating pathways involved in trimethylamine (TMA) synthesis. This microbial shift led to a systemic increase in the metabolite trimethylamine N-oxide (TMAO) and its accumulation in the hippocampus. Mechanistic experiments revealed that TMAO drives neurotoxicity by activating the hippocampal PERK-mediated endoplasmic reticulum (ER) stress pathway. Critically, these deficits were reversed by suppressing hepatic TMAO production via either pharmacological inhibitors or genetic knockdown. Additionally, hippocampal-specific PERK silencing or dietary resveratrol intervention attenuated hippocampal ER stress, thereby protecting against PM2.5-induced cognitive and hippocampal impairments. These results identify the microbial metabolite TMAO as a key mediator of air pollution-related neurotoxicity and highlight the gut-liver-brain axis as a promising therapeutic strategy to counteract the neurological impacts of air pollution.

animal behavior and cognition↗

bioRxiv2026

Modeling Prenatal Immune Activation in Human Brain Organoids Uncovers IL-6-Dependent Interneuron Dysmaturation

Prenatal inflammation has been associated with an increased likelihood of the child developing neurodevelopmental conditions, such as autism spectrum disorder (ASD). Several pro-inflammatory cytokines are significantly upregulated and play critical roles during immune activation, with interleukin-6 (IL-6) being particularly prominent. However, the specific impact of elevated IL-6 levels on human neural development remains to be elucidated. To address this, we established a human pluripotent stem cell-based forebrain organoid model enriched for multiple interneuron lineages, validated through immunohistochemistry and transcriptomic alignment with human fetal reference datasets. We showed IL-6 responsiveness via the activation of the JAK/STAT pathway and characterized downstream effects using bulk and single-nucleus RNA sequencing (RNA-seq). Bulk RNA-seq at the end of IL-6 exposure uncovered activation of inflammatory pathways, upregulation of MHC-I machinery, and early disruption of GABAergic signaling programs. Notably, single-nucleus RNA-sequencing performed one month after IL-6 withdrawal revealed a persistent inflammatory transcriptional signature across interneuron development, accompanied by accelerated progression through maturation stages and altered interneuron subtype output. Together, these findings demonstrate that transient prenatal IL-6 exposure is sufficient to reshape human interneuron fate specification and maturation trajectories, providing mechanistic insights into neuroimmune contributions to ASD.

neuroscience↗

bioRxiv2026

Comprehensive Complete-Genome Analysis of Lactobacillaceae and Bifidobacteriaceae Reveals Strain-Specific Metabolic Interactions in Chinese Gut Microbiota

Bifidobacteriaceae and Lactobacillaceae are key probiotic families and widely used in food production, yet a comprehensive understanding of strain functions and their gut microbial interactions based on complete genomes remain understudied. Here we constructed a complete-genome dataset of 3,300 strains from these two families, including 1,151 newly isolated from China. Compared with draft assemblies, complete genomes substantially recovered a gene functional landscape encompassing stress tolerance, surface exopolysaccharide synthesis, nutrient utilization, and mobile genetic elements. Major species from both families exhibited a prevalence >60% in the Chinese population, far higher than that in US/Dutch cohorts. Notably, as a core probiotic species with remarkable genomic plasticity and gut-adaptive potential, Lactiplantibacillus plantarum stood out in our dataset for its enriched functional profile and was particularly abundant in the Chinese population. Moreover, compared with non-Chinese genomes, our isolates of key species displayed less metabolic complementarity and stronger competition with potentially pathogenic keystone species in the gut, thereby linking strain origin to enhanced probiotic potential and ecological fitness to benefit human gut health.

microbiology↗

bioRxiv2026

Control of Oxidative Stress and Intracellular Survival in Francisella tularensis Live Vaccine Strain (LVS) via Acyl-CoA Synthetase

Francisella tularensis is a highly infectious, Gram-negative intracellular bacterium and the causative agent of tularemia, a potentially fatal disease. Owing to its low infectious dose, ease of aerosolization, high virulence, lack of an effective vaccine, and potential use as a bioterrorism agent, F. tularensis is classified by the CDC as a Tier 1 Category A Select Agent. Despite its clinical importance, the mechanisms underlying F. tularensis virulence remain incompletely understood. In this study, we generated a partial Tn5 transposon insertion mutant library in the F. tularensis live vaccine strain (LVS) and identified a mutant disrupted in the FTL_0690 gene through screening under macrophage-like conditions. FTL_0690 encodes an acyl-CoA synthetase. Characterization of both a transposon-insertion mutant and a targeted deletion mutant ({Delta}FTL_0690) revealed critical roles for this enzyme in F. tularensis pathobiology. Loss of FTL_0690 increased sensitivity to oxidative stress and impaired intracellular growth within macrophages compared to wild-type F. tularensis LVS. Lipidomic profiling of the {Delta}FTL_0690 mutant revealed disruptions in fatty acid metabolism, membrane lipid remodeling, and redox homeostasis. Altered lipid-derived and membrane-associated metabolites indicated defective phospholipid incorporation and altered membrane composition, likely contributing to oxidative stress sensitivity and reduced intramacrophage survival. Collectively, these findings demonstrate that FTL_0690 which encodes long-chain acyl-CoA synthetase, contributes to lipid homeostasis, membrane integrity, and oxidative stress resistance of F. tularensis. ImportanceThis work addresses critical gaps in our understanding of Francisella tularensis virulence by identifying lipid metabolism as a central determinant of intracellular survival and stress resistance. By integrating transposon mutagenesis, targeted gene deletion, and lipidomic profiling, this study provides mechanistic insight into how metabolic remodeling supports pathogenesis. Our identification and characterization of FTL_0690 as a long-chain acyl-CoA synthetase essential for lipid homeostasis, membrane integrity, and oxidative stress resistance reveals a previously unappreciated link between fatty acid metabolism and intramacrophage survival of F. tularensis.

microbiology↗

bioRxiv2026

IL-36γ Drives Th9 cell Differentiation via IκBζ to Sustain Antitumor Immunity

Th9/Tc9 cells polarized with TGF-{beta} and IL-4 exhibit superior antitumor efficacy, prompting extensive efforts to optimize their differentiation protocols and augment therapeutic potency. In the current study, we identified IL-36{gamma} as a potent cytokine that synergizes with TGF-{beta} to robustly drive Th9 differentiation both in the presence and absence of IL-4. IL-36{gamma}-programmed Th9 cell subsets exhibited phenotypic and transcriptional profiles identical to classic Th9 cells. Mechanistically, IL-36{gamma} drove Th9 cell differentiation through amplifying key signaling pathways such as STAT6, STAT5, and NF-{kappa}B that are essential for classic Th9 programming. Notably, we uncovered a novel regulatory axis wherein IL-36{gamma} upregulates the transactivation factor I{kappa}B{zeta}, which directly governs Th9 lineage specification. In in adoptive cell therapy (ACT) models, IL-36{gamma}-polarized Th9 cell subsets demonstrated enhanced antitumor efficacy, attributable to their sustained persistence, reduced exhaustion markers and stem-like/memory properties. Collectively, this study elucidates a previously unrecognized I{kappa}B{zeta}-dependent mechanism underpinning Th9 differentiation and highlights the translational potential of IL-36{gamma}-engineered Th9 cells as a valuable ACT strategy for refractory tumors.

immunology↗

bioRxiv2026

A Deep Learning-Based Scoring Framework for Large-Scale Multi-Donor Cardiotoxicity Screening

Cardiotoxicity remains a major cause of drug attrition and post-market withdrawal, yet the vast majority of environmental chemicals to which humans may be exposed remain uncharacterized for cardiotoxicity risk. Human induced pluripotent stem cell (hiPSC)-based testing has been proposed to address this gap. Here we present an unsupervised deep learning framework for multi-donor cardiotoxicity screening using high-throughput calcium transient recordings from hiPSC-derived cardiomyocytes (hiPSC-CMs). We used data from a library of 1,029 compounds that were tested in hiPSC-CM from five donors in concentration-response. An autoencoder trained exclusively on baseline signals quantified chemical-induced functional perturbations through reconstruction error, bypassing the need for labeled training data while capturing the full spectrum of calcium handling disruptions. Using this framework, we generated effect levels. Aggregation of donor-specific scores revealed substantial inter-individual variability in potential cardiotoxicity, underscoring the value of this approach for population-level risk prediction. We found that microbiocides, dyes, and pesticides to have potential concern, characterized by high toxicity scores and low inter-donor variability. This framework establishes a scalable, human-relevant, and genetically diverse platform for cardiotoxicity surveillance across both pharmacological and environmental chemical spaces, with direct implications for drug and chemical safety evaluation and prioritization for additional studies.

bioengineering↗

bioRxiv2026

Targeted medial prefrontal cortex stimulation prevents incubation of cocaine craving and restores functional connectivity

BackgroundRelapse remains a central obstacle in the treatment of cocaine use disorder (CUD), for which no medications have received approval from the U.S. Food and Drug Administration. Transcranial magnetic stimulation (TMS) has shown promise as a potential therapeutic intervention. However, current clinical trials often rely on a "trial-and-error" approach in target selection and experimental design. We previously developed a novel TMS platform and high-density theta burst stimulation (hdTBS) technology, enabling precise, focal stimulation of the rat medial prefrontal cortex (mPFC), including the prelimbic and anterior cingulate cortices. MethodsWe applied hdTBS intervention to a well-established rat model of cocaine relapse and craving after cessation of extended access intravenous drug self-administration and assessed brain response using resting-state functional magnetic resonance imaging (fMRI). ResultsAs expected, we observed robust time-dependent increases in cocaine seeking (incubation of cocaine craving) in control rats receiving sham stimulation over 3 weeks of abstinence accompanied by a reduction in prefrontal functional connectivity. In contrast, daily sessions of hdTBS for 7 days delivered on abstinence days 14-20 prevented the emergence of the incubation effect and restored prefrontal network functional connectivity. ConclusionsThis study provides strong preclinical evidence demonstrating that precise circuit modulation of medial prefrontal subregions causally reverses both behavioral and network-level adaptations associated with relapse vulnerability. Given the clinical accessibility and established safety profile of TMS, this work provides a mechanistically grounded framework for target selection and supports the translation of focal TMS of the mPFC for relapse prevention in CUD patient. One Sentence SummaryFocal transcranial magnetic stimulation (TMS) of the mPFC using the hdTBS procedure prevents incubation of cocaine craving and restores functional connectivity.

neuroscience↗

bioRxiv2026

A Generative AI Framework to Predict Cardiomyocyte Contraction Function from Single Static Images.

Understanding how cardiomyocyte structure governs contractile function is fundamental to cardiac biology and disease modeling, yet current approaches rely on time-resolved imaging and computationally intensive analysis. Here, we present a generative artificial intelligence (AI) framework that directly predicts contractile behavior of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from single static images. Our approach integrates a U-Net-based generator with a patch-based generative adversarial network (GAN) discriminator to translate morphological and sarcomere structural features into pixel-resolved contraction heatmaps. This U-Net-GAN model achieved high predictive accuracy, with structural similarity index (SSIM) values up to 0.84 using combined morphological and structural inputs. To further enhance performance and generalizability, we incorporated synthetic cell-function pairs generated via a generative AI StyleGAN2 framework, improving prediction accuracy and perceptual similarity. Importantly, region-specific and whole-cell analyses revealed that AI predictions capture biologically meaningful structure-function relationships, with sarcomere organization strongly associated with both contractile output and prediction fidelity. Reconstruction error emerged as an interpretable metric reflecting localized inefficiencies in sarcomere-to-contraction coupling. Together, this framework establishes a scalable and interpretable strategy for inferring cardiomyocyte function from static morphology, eliminating the need for time-lapse imaging. More broadly, this work positions generative AI as a powerful tool for bridging cellular structure and function, enabling high-throughput functional phenotyping and advancing in vitro cardiac modeling.

bioengineering↗

bioRxiv2026

A Fungal Natural Product that Targets Cellulose Synthase Complex and Inhibits Plant Cellulose Biosynthesis

Cellulose, a primary component of plant cell walls, is synthesized by cellulose synthase complexes (CSCs) at the plasma membrane. Targeting this process with cellulose biosynthesis inhibitors (CBIs) has significantly advanced our understanding of plant cell wall formation and provided valuable compounds for herbicide development. Here, we identified a fungal natural product, 8-methyldichlorodiaporthin (MDD), as a broad-spectrum plant CBI. Structure-activity relationship analyses demonstrate that methylation modifications on the isocoumarin ring and chlorination of side chain are crucial for MDD-induced growth inhibition. A chemical forward genetic screen in Arabidopsis thaliana revealed two semi-dominant CESA1 mutations, causing A903T and H1024Y substitutions, that confer insensitivity to MDD. Both mutations locate to transmembrane domains of CESA1, and we show that MDD depletes CSCs from the plasma membrane and reduces cellulose content. Further genetic analyses indicate that the cesa1mddi1-1 A903T mutant also confers resistance to CBIs quinoxyphen and C17, but not to CBIs isoxaben, indaziflam, or ES20. Stacking additional point mutations conferring resistance to other CBIs, cesa3ixr1-1 G998D, and cesa6es20-r3 G935E into the cesa1mddi1-1 A903T background yields multiple-drugs resistant lines that maintain normal growth. These findings establish MDD, as a novel, natural CBI that likely targets CESA1, thereby extending our understanding of CSC regulation and abilities to develop multi-drugs resistant crop varieties. These findings offer new perspectives for weed management and plant biotechnology. Significance StatementCellulose, a fundamental structural component of plant cell walls, is synthesized by cellulose synthase complexes (CSCs) and represents a critical herbicide target. While synthetic cellulose biosynthesis inhibitors (CBIs) like isoxaben and quinoxyphen have helped in the elucidation of CSC function and aided in weed control, natural CBIs remain largely undiscovered. Here, we identify 8-methyldichlorodiaporthin (MDD), a fungal-derived isocoumarin natural product, as a CBI that inhibits plant growth by depleting CSCs from the plasma membrane. Genetic screens reveal MDD-resistant cesa1 mutations, and combining these with other CBI-resistant alleles yields multi-herbicide resistant plants that can grow normally. This research enhances our understanding of cellulose biosynthesis and paves the way for multi-herbicide resistant crops with agricultural benefits.

plant biology↗

bioRxiv2026

Antioxidant defenses of Francisella tularensis perturb Aim2 Inflammasome Activation

Francisella tularensis is a Gram-negative bacterium that causes tularemia, a fatal zoonotic disease. F. tularensis has been used in the bioweapon programs of several countries. Its potential use as a bioterrorism agent led the CDC to classify F. tularensis as a Tier 1 Select Agent. The cytosolic sensor absent in melanoma 2 (Aim2) detects double-stranded DNA in the cytosol of infected cells and subsequently assembles a multiprotein complex known as the inflammasome. Inflammasome activation drives the secretion of IL-1{beta} and IL-18, key proinflammatory cytokines required for controlling F. tularensis infection. Prior studies have shown that F. tularensis actively suppresses Aim2 inflammasome activation; however, the underlying mechanism remains unknown. We hypothesized that F. tularensis suppresses Aim2-mediated responses by modulating the intracellular redox environment. We utilized an F. tularensis mutant lacking OxyR ({Delta}oxyR), a transcriptional regulator that controls the expression of major antioxidant enzymes. Our results show that macrophages infected with the {Delta}oxyR mutant exhibit significantly higher levels of Aim2-dependent Caspase-1 and IL-1{beta} than those infected with wild-type bacteria. The expression of interferon regulatory factor 1 and the guanylate-binding proteins GBP2 and GBP5, upstream signaling components of the Aim2 inflammasome, is markedly higher in {Delta}oxyR-infected macrophages than in controls. These changes were absent in {Delta}oxyR-infected NADPH oxidase-deficient macrophages, which are unable to generate reactive oxygen species. Collectively, these findings demonstrate that macrophage redox environment plays a key role in activating signaling components required for Aim2 inflammasome activation. This work advances our understanding of how F. tularensis-encoded factors subvert host innate immune defenses.

immunology↗

bioRxiv2026

Celastrol alleviates SGLT2 inhibitor-induced diabetic hyperketonemia by inhibiting hepatic ketogenesis

SGLT2 inhibitor (SGLT2i)-induced diabetic hyperketonemia is a life-threatening acute complication of diabetes. While Celastrol has been reported to exert beneficial effects on obesity; its potential role in ketogenesis remains unclear. In this study, Celastrol administration significantly attenuates the fasting-induced elevation of blood {beta}-hydroxybutyrate. Moreover, a 7-day course of Celastrol (1 mg/kg/day) leads to reductions in body weight and fat mass. Mechanistically, Celastrol specifically downregulates HMGCS2 expression and suppressess hepatic ketogenesis through inhibiting PPAR expression in the short term ([≤] 2 days). However, after prolonged treatment for 7 days, Celastrol modulates both PPARand serum free fatty acids (FFAs) levels. Furthermore, anti-ketogenic effect of Celastrol is abolished in Ppar{square} /{square} mice. Importantly, Celastrol effectively ameliorates SGLT2i-induced hyperketonemia. In summary, Celastrol curbs hepatic ketone overproduction in a PPAR-dependent manner, indicating its protective potential against SGLT2i-induced hyperketonemia.

molecular biology↗